Tackling Autoimmune Disease with Cell and Gene Therapy

Over the last decade, the cell and gene therapy space has changed beyond recognition. The field has experienced ups and downs, but such advanced therapeutics are becoming more mainstream and moving into spaces outside cancer and rare diseases.

At the end of 2015, only three cell and gene therapy products had been approved by the FDA. By the end of 2024, this figure had increased to 43 products, with more therapies approved every year.

Notable successes to date are chimeric antigen receptor (CAR) T cell therapies for treating different cancers, of which seven have been approved so far. Other examples are gene therapies such as Spark Therapeutics’ Luxturna for treating inherited retinal disease, Novartis’ Zolgensma for treating children with spinal muscular atrophy, and Casgevy, the first CRISPR gene-edited therapeutic for sickle cell disease and transfusion-dependent beta thalassemia, developed by CRISPR Therapeutics and Vertex Pharmaceuticals.

At present, the FDA-approved therapies are focused on treating cancers and rare diseases, but this is starting to change. A report published in the second half of last year by the American Society of Gene and Cell Therapy showed that 51% of new gene therapy trials are focused on indications other than cancer, compared with 39% the year before.

Similarly, while the majority of gene and cell therapy human trials (700) focused on rare disease indications in Q4 of 2024, 640 Phase I–III trials focused on prevalent conditions, according to a report from the Alliance for Regenerative Medicine.

New gene editing options like CRISPR, as well as improved manufacturing and vector technology are helping gene and cell therapy move on to newer and more prevalent indications beyond cancer and rare disease.

“Now, we have technology that enables us to still use sophisticated and complex methods for cell and gene therapy, but in a more scaled up and scaled out manner so you can think about more indications,” explained Miloš Miljković, MD, chief medical officer at Cartesian Therapeutics in Maryland, which is developing cell therapies for autoimmune diseases.

Advanced therapeutics have the potential to be more precise than currently available biologic medicines for treating autoimmunity, and could even cure conditions like type 1 diabetes if given at an early stage. Recent positive results in human trials have given hope to the field, with many companies and academic teams competing to be the first to market with cell or gene therapies for type 1 diabetes, myasthenia gravis, rheumatoid arthritis, and other autoimmune conditions.

Repurposing CAR T cell therapy

A key breakthrough that triggered a lot of interest in cell and gene therapies for treating autoimmune disease occurred in 2022 when George Schett, MD, vice president for research at the Friedrich-Alexander-Universität Erlangen-Nürnberg in Germany, decided to test whether CAR T cell therapy could be used to treat autoimmune conditions.

Schett, an immunologist and rheumatologist, recognized that CAR T cell therapies that target malignant B cells in leukemia and lymphoma could also treat diseases like lupus, where B cells in the body become pathogenic and attack the body’s own cells. This insight led to his addition to the 2024 Time magazine list of the most influential people in health.

The initial study carried out by Schett and colleagues included a small number of patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis. Using a similar protocol to that used for cancer patients, the patients in the study received CD19 CAR T cell therapy and were then followed up for up to 29 months. The results were remarkable, with all the SLE patients achieving remission and stopping other therapies. Promising improvements were also seen in the non-lupus patients.

Several companies, including CRISPR Therapeutics, are now working on both autologous CAR T cell therapies, where the cells are extracted from and reinfused into the patient, and “off-the-shelf” or allogeneic therapies, which are made from donor cells, to treat autoimmune conditions.

“What was noted [in Schett’s study] is that the CAR T cell therapy causes a profound depletion of pathogenic B cells even in deep lymphoid tissues, and when the B cells return, they are naïve and no longer pathogenic. It is believed that this may be the mechanism of how the CAR T cell therapy resets the immune response, to provide long-term remission,” explained Naimish Patel, MD, chief medical officer of CRISPR Therapeutics.

“This durable remission has never been seen in biologics, whether they be mono- or bispecifics, and this has been seen in most patients treated by the Schett group and others.”

CRISPR Therapeutics is developing several therapies for autoimmune diseases, including a gene edited CAR T cell therapy called CTX112 for the treatment of both cancer and autoimmune diseases. After being tested in patients with B cell malignancies to assess safety, it is currently in a Phase I trial in patients with SLE, systemic sclerosis, and inflammatory myositis to try and replicate the effects observed by Schett and team.

“CTX112 … allows for deep B cell depletion and it is off-the-shelf technology, which is significantly less costly, and patients can proceed quickly to therapy without the need to come off their autoimmune disease therapy for a prolonged period of time,” said Patel. “Many patients with SLE also have low lymphocyte counts at baseline, making them unsuitable for T cell harvesting that is required for autologous CAR T cell therapy.”

A different patient population

Although the results achieved by Schett in SLE patients were unprecedented, there are significant disadvantages to using standard CAR T cell therapy in patients with autoimmune diseases.

“The drawbacks to autologous CAR T cell therapies are that they are very expensive, require patients to stop their immunomodulatory therapy to get T cells harvested, have not been widely available, particularly in community settings, and are associated with potentially severe side effects such cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS),” said Patel.

For this reason, biotech companies working in this space are making alterations to CAR T-like cell therapies to try and reduce costs, improve patient quality of life, and allow for wider rollout should they be approved.

CTX112 is not a typical CAR T cell therapy, it is off-the-shelf and has higher potency and lower side effects than other CD19-targeting candidates. However, it is still essentially similar to the original CD19 therapies approved to treat blood cancer. Cartesian Therapeutics is moving even further away from the original therapies in this class and has created an mRNA CAR T cell therapy. Its lead candidate, Descartes-08, is in Phase II trials for myasthenia gravis and a Phase I trial for SLE.

Traditional CAR T cell therapy uses lentiviral or retroviral vectors to permanently change the CAR on the patients’ T cells, whereas by using mRNA, the T cells are only changed for a short time. The cells do not extensively proliferate in the body and are instead expanded “ex vivo” in the lab before injecting them.

“When you use mRNA, you’re expanding the cells ex vivo. You don’t rely on in vivo proliferation, so you don’t need to use lymphodepletion chemotherapy to create the right cytokine environment,” explained Miljković.

“You don’t have risk of cytokine release syndrome or ICANS, so you can have outpatient administration with just one hour of post-infusion monitoring.”

In addition to being safer and easier for patients, using mRNA to create CAR T cell therapy makes it easier to control. It also has the potential for improved efficacy and, through simpler manufacturing and treatment procedures, is a more cost-effective option.

In a Phase IIb trial reported last summer, Cartesian’s lead therapy achieved its primary endpoint of an improvement in the MG Composite score for patients with generalized myasthenia gravis, a condition that leads to muscle weakness because immune cells mistakenly attack neuromuscular junctions. The company is now planning to run a Phase III trial of Descartes-08 this year.

Colorado-based RheumaGen is also developing a cell therapy for autoimmune disease, but is focusing on T cell rather than B cell-mediated conditions. It is combining gene editing and cell therapy to treat autoimmune conditions caused by mutations in the human leukocyte antigen (HLA) gene, such as rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. The company’s lead therapeutic candidate, RG0401, is designed to treat people with rheumatoid arthritis that does not respond to other treatments (10–20% of cases).

RheumaGen is using hematopoietic stem cells from the patient’s blood and gene editing technology to “correct” gene variants in the HLA gene that cause symptoms of autoimmunity. The stem cells go into the bloodstream, migrate to the bone marrow, and take up residence. They then produce antigen-presenting cells that can no longer trigger autoimmune reactions.

“We’ve now found a single target that is common across all class II HLA, so that acts like an anchor point. … Think of it like breaking the bottom of a zipper. So even though there’s a bunch of other binding points along the groove, if that spot isn’t bound, the whole thing kind of falls apart. Essentially, it turns off all peptide binding for that particular HLA allele that’s causing all the problems,” explained company CEO and co-founder Richard Freed.

“You still have your 12 or 13 other HLA alleles that provide lots of cross coverage, so it’s much less immunosuppressive than taking Humira, for example. … We’re just essentially turning the one bad actor down by about 90%.”

Similar to Cartesian, RheumaGen is planning to dose its therapy in an outpatient setting. Both autologous and allogeneic stem cell transplants have been tried for severe rheumatoid arthritis in the past, but with limited success as autologous transplants only work for a short time and allogeneic transplants come with rejection risks.

“What we’re doing is kind of giving the treatment benefits and the proven curative benefits of the allogeneic transplant, but with the safety of the autologous transplant,” said Freed.

Although RheumaGen is at an earlier stage than Cartesian and is yet to enter clinical trials, the preclinical results are promising. “It worked great in the mice. We’ve shown that we can completely stop the ability to present collagen,” said Freed.

The company is also aiming to develop additional candidate therapies for multiple sclerosis and type 1 diabetes, but will initially focus on getting its rheumatoid arthritis candidate into clinical trials. “If all goes according to plan, we’ll submit our IND to the FDA sometime late this year,” explained Freed.

Harnessing tolerization to treat autoimmune disease

The immune system’s ability to fight off pathogens through different processes is well known. However, in addition to responding to potential pathogens, the immune system develops and maintains unresponsiveness to specific non-harmful antigens through an active process called tolerization.

In people with autoimmune diseases, tolerization does not work as it should. Antigens that should be recognized as “self” are seen as pathogens that need to be destroyed.

Central tolerance occurs in the white blood cells as they develop. Both the thymus and bone marrow play a role in “training” B and T cells to correctly recognize safe antigens. T regulatory cells help maintain peripheral tolerization by suppressing self-reactive T cells that have escaped central tolerance mechanisms in the thymus.

This process is something that Gdańsk-based PolTREG are harnessing to fight type 1 diabetes. “The basic idea behind the treatment is that in autoimmune diseases, like type 1 diabetes, there is a defect in the tolerance system. These people lack activity or sufficient numbers of T regulatory cells,” explained PolTREG CEO and co-founder Piotr Trzonkowski, MD, PhD.

The company was founded in 2015 as a spin-off from the Medical University of Gdańsk and has already advanced four projects in type 1 diabetes and multiple sclerosis to clinical trials, although the lead indication for its T regulatory cell therapy PTG-007 is type 1 diabetes.

PTG-007 is an autologous therapy where the patient’s own T regulatory cells are extracted from their blood and expanded outside the body. The cells are then reinjected to target the fault in tolerization that occurs in autoimmune diseases like type 1 diabetes.

“If you add the T regulatory cells that are able to stop this autoaggression, then you have either diminished intensity of symptoms, or you can basically stop or prevent the disease if you do it really, really quickly,” said Trzonkowski.

The initial research, started by the scientific founders at the university, has now accrued 12 years of follow-up data in a study of patients with early-stage type 1 diabetes who received treatment with PTG-007. These individuals were in remission for several years and continued to secrete insulin after the treatment, whereas control patients did not. Notably, side effects are minimal with this cell therapy, unlike with CAR T cell therapy.

Using this initial study in early-stage patients as proof of concept, PolTREG is now conducting a trial to prevent the onset of type 1 diabetes altogether in people at high risk of developing the condition (i.e., with several autoantibodies and a family history of diabetes).

“For the patient, it means that if it works, they will never develop the disease. They will always be at risk, clinically, medically, but it means that if the therapy works, they will never develop the symptoms, so they will be healthy,” said Trzonkowski.

PolTREG has its own manufacturing facility in Gdańsk and a number of other therapies in development, including an off-the-shelf version of PTG-007. The company is modifying the cells to make them less likely to be rejected, making patients less dependent on long-term immunosuppressive drugs.

Amarna Therapeutics, based in Leiden, is also harnessing tolerization to treat type 1 diabetes, but is taking a gene therapy route and using a viral vector to mediate tolerization.

The company’s lead candidate, Nimvek AM510, uses a polyoma viral vector. “It aims to address the root cause of type 1 diabetes by restoring immune tolerance to proinsulin, which is the primary self-antigen involved in the autoimmune destruction of beta cells,” explained chief business officer Aurelia Caparrós. “It not only has not the potential to halt progression of the disease, but also to cure it, and hopefully even to completely prevent the disease from occurring at all.”

To date, many companies and researchers working in the gene therapy space have and are still using adeno-associated viral (AAV) vectors. While these vectors can be effective for some indications, they are expensive to produce and trigger immune responses in many people.

In contrast, polyoma viruses are small circular DNA viruses that do not trigger immune reactions. “They are cryptic viruses,” explained the chief scientific officer and co-founder of Amarna, Peter de Haan, PhD. “They infect you, cause symptomless infections, and you transfer them at a certain moment in time to another person. But it remains completely under the immune radar, so they are very suitable for use as gene therapy vectors.”

In the 1950s and 1960s, several batches of polio vaccine were found to be contaminated with a polyoma virus, SV40. There was much concern at the time that this might have had adverse effects on those given the contaminated vaccine, but to date no health issues have been linked to this exposure.

“With our vector that induces an immune tolerance response to, for example, pro-insulin, we can suppress the T lymphocytes in the pancreas by inducing what we call regulatory T lymphocytes, specific for pro-insulin, in the liver,” explained de Haan.

“T regulatory cells will be induced that migrate to the pancreas because there is inflammation there and immune cells migrate to inflammation. We have induced pro-insulin-specific T regulatory cells in the liver, and these cells will inhibit the T cells that destroy the beta cells in an antigen-specific manner.”

Amarna is still in the preclinical stages of development, but has good results in animals that show the therapy could be used both as a treatment and a potential preventative measure to stop autoimmunity from developing in people at risk of type 1 diabetes.

Prime time for cell and gene therapy

The cell and gene therapy space is expanding fast. This year, the market value for the sector is set to reach $25 billion, compared with $18 billion in 2023, and more than double by 2030.

Now that early therapies have been approved by regulators and shown to be successful, moving on to bigger indications like autoimmune disease is a logical next step for the gene and cell therapy space. However, it is not without its challenges.

Patients with autoimmune diseases are often not as sick as people with advanced stage cancer or life-threatening rare diseases, making safety and efficacy a key focus. “You must have a longer trials, usually these protocols are much more complicated, often the endpoints have to be much more exceptional,” explained Trzonkowski.

“Here, you also need to think about the quality of life. You cannot just give the treatment. … You also need to care about the patient because this is the disease which will be with the patient for his or her whole life.”

These additional considerations make clinical trials challenging and more expensive than earlier rare disease and cancer trials, especially at the later stages. But for companies that get to the end of the long road to market approval, the potential payoffs are large.

Some early gene therapies have become notorious for the large amount of money they charge per patient. Treating more patients could help make the therapies more affordable in the long run, which could help make cell and gene therapies more acceptable to payers.

“From an access standpoint, there are only a few places that can afford such huge and expensive treatments,” notes Caparrós. “The cost of goods with AM510 will be much, much lower so we can really address that particular disease and also give the option to as many patients as possible, which could be much more affordable to the health authorities than the current available options.”

Looking to the future of gene therapy, much investment and time has been put into AAV vectors over the last decade, but it is becoming clear that although they are useful in some indications, AAVs have a number of problems. For example, they are expensive to produce and are generally not ideal for treating more prevalent conditions. New vectors, such as those being pioneered by EG 427 and Amarna, are needed to improve specificity, safety, and dosing.

“AAV vectors can only take limited amount of genetic material, around 4.6 kb, and they are highly immunogenic,” explained Philippe Chambon, MD, PhD, CEO of EG 427. “For most indications, you need to treat the patient for a rather extended period of time with a heavy dose of corticosteroid to avoid major side effects.”

In cell therapy, moving to off-the-shelf options for things like CART cell therapy is becoming closer to reality. New technologies such as CRISPR-based gene editing are also making it easier to engineer cells to improve potency and reduce side effects.

“The next great frontier for these technologies will involve next-generation editing and delivery modalities, such as all-RNA gene correction, whole gene insertion, and non-viral delivery of DNA,” said Patel. “Our CRISPR-X team based in San Francisco and Boston is a group focused on emerging technologies in all these areas.”

Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. Prior to going freelance, she was editor-in-chief at Labiotech, an English-language, digital publication based in Berlin focusing on the European biotech industry. Before moving to Germany, she worked at a range of different science and health-focused publications in London. She was editor of The Biochemist magazine and blog, but also worked as a senior reporter at Springer Nature’s medwireNews for a number of years, as well as freelancing for various international publications. She has written for New Scientist, Chemistry World, Biodesigned, The BMJ, Forbes, Science Business, Cosmos magazine, and GEN. Helen has academic degrees in genetics and anthropology, and also spent some time early in her career working at the Sanger Institute in Cambridge before deciding to move into journalism.